Synthesis of 1,1-disubstituted alkyl vinyl sulfides via rhodium-catalyzed alkyne hydrothiolation: Scope and limitations

Article abstract of DOI:10.1021/jo801644s

(Chemical Equation Presented) Described herein are the scope and limitations using Tp*Rh(PPh₃)₂ as a catalyst for alkyne hydrothiolation with alkyl thiols. In general, catalytic hydrothiolation proceeds in high yields and with high regioselectivity for a wide range of alkynes and thiols. A variety of functional groups were well-tolerated, including nitriles, amines, halogens, ethers, esters and silanes, although strongly coordinating groups were found to be incompatible with hydrothiolation. Both sterically encumbered alkynes and thiols were successful in hydrothiolation. Electron rich alkynes react more rapidly than electron deficient alkynes. Overall, this hydrothiolation protocol provides convenient access to a variety of functionalized branched alkyl vinyl sulfides.

Full text of DOI:10.1021/jo801644s

Synthesis of 1,1-Disubstituted Alkyl Vinyl Sulfides via
Rhodium-Catalyzed Alkyne Hydrothiolation: Scope and Limitations
Jun Yang, Anthony Sabarre, Lauren R. Fraser, Brian O. Patrick, and Jennifer A. Love*
Department of Chemistry, 2036 Main Mall, UniVersity of British Columbia, VancouVer, British Columbia
V6T 1Z1, Canada
jenloVe@chem.ubc.ca
ReceiVed August 12, 2008
Described herein are the scope and limitations using Tp*Rh(PPh3)2 as a catalyst for alkyne hydrothiolation
with alkyl thiols. In general, catalytic hydrothiolation proceeds in high yields and with high regioselectivity
for a wide range of alkynes and thiols. A variety of functional groups were well-tolerated, including nitriles,
amines, halogens, ethers, esters and silanes, although strongly coordinating groups were found to be incompatible
with hydrothiolation. Both sterically encumbered alkynes and thiols were successful in hydrothiolation. Electron
rich alkynes react more rapidly than electron deficient alkynes. Overall, this hydrothiolation protocol provides
convenient access to a variety of functionalized branched alkyl vinyl sulfides.
Introduction
thiols has been achieved in radical,5 nucleophilic,6 and metal-
catalyzed7 reactions, alkyl thiols are typically found to be
unreactive.7g A selective method for the formation of Z-linear
vinyl sulfides emerged in 2005,6e yet a general method for the
stereo- and regiocontrolled synthesis of either branched and
E-linear alkyl vinyl sulfides remained an unmet goal.
Vinyl sulfides are valuable synthetic intermediates in total
synthesis1 and are versatile building blocks2 for many func-
tionalized molecules. Many natural products and compounds
exhibiting interesting biological properties contain an alkyl vinyl
sulfide moiety.3 For example, griseoviridin is a broad spectrum
antibiotic with in vitro inhibitory activity against various
pathogenic microorganisms.4 As such, strategies for the con-
struction of alkyl vinyl sulfides are highly desirable.
An attractive method for the formation of vinyl sulfides
involves hydrothiolation, the reaction of an S-H bond across
an alkynyl π-bond (eq 1). Although hydrothiolation with aryl
We anticipated that the use of a suitable transition metal
complex would overcome the substrate limitations for catalytic
(1) For examples of vinyl sulfides as intermediates in total synthesis, see:
(a) Bratz, M.; Bullock, W. H.; Overman, L. E.; Takemoto, T. J. Am. Chem. Soc.
1995, 117, 5958–5966. (b) Mizuno, H.; Domon, K.; Masuya, K.; Tanino, K.;
Kuwajima, I. J. Org. Chem. 1999, 64, 2648–2656. (c) Pearson, W. H.; Lee,
I. Y.; Mi, Y.; Stoy, P. J. Org. Chem. 2004, 69, 9109–9122.
(2) For examples of vinyl sulfides as synthetic intermediates or precursors
to functionalized molecules, see: (a) Parham, W. E.; Motter, R. F. J. Am. Chem.
Soc. 1958, 81, 2146–2148. (b) Mukaiyama, T.; Kamio, K.; Kobayashi, S.; Takei,
H. Bull. Chem. Soc. Jpn. 1972, 4, 193–202. (c) McClelland, R. A. Can. J. Chem.
1977, 55, 548–551. (d) Wenkert, E.; Ferreira, T. W.; Michelotti, E. L. J. Chem.
Soc., Chem. Commun. 1979, 6, 637–638. (e) Trost, B. M.; Lavoie, A. C. J. Am.
Chem. Soc. 1983, 105, 5075–5090. (f) Sabarre, A.; Love, J. A. Org. Lett. 2008,
10, 3941–3944.
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bioactive molecules, see: (a) Sader, H. S.; Johnson, D. M.; Jones, R. N.
Antimicrob. Agents Chemother. 2004, 48, 53–62. (b) Johannesson, P.; Lindeberg,
G.; Johansson, A.; Nikiforovich, G. V.; Gogoll, A.; Synnergren, B.; Le Greves,
M.; Nyberg, F.; Karlen, A.; Hallberg, A. J. Med. Chem. 2002, 45, 1767–1777.
(c) Ceruti, M.; Balliano, G.; Rocco, F.; Milla, P.; Arpicco, S.; Cattel, L.; Viola,
F. Lipids 2001, 36, 629–636. (d) Marcantoni, E.; Massaccesi, M.; Petrini, M.;
Bartoli, G.; Bellucci, M. C.; Bosco, M.; Sambri, L. J. Org. Chem. 2000, 65,
4553–4559. (e) Lam, H. W.; Cooke, P. A.; Pattenden, G.; Bandaranayake, W. M.;
Wickramasinghe, W. A. J. Chem. Soc., Perkin Trans. 1 1999, 847–848. (f)
Morimoto, K.; Tsuji, K.; Iio, T.; Miyata, N.; Uchida, A.; Osawa, R.; Kitsutaka,
H.; Takahashi, A. Carcinogenesis 1991, 12, 703–708.
182 J. Org. Chem. 2009, 74, 182–187
10.1021/jo801644s CCC: $40.75 2009 American Chemical Society
Published on Web 11/24/2008

Synthesis of 1,1-Disubstituted Alkyl Vinyl Sulfides
TABLE 1. Scope of Hydrothiolation of Aryl Alkynes with
Benzylthiol Catalyzed by I
FIGURE 1. Complex I, Tp*Rh(PPh3)2.
hydrothiolation. Accordingly, we recently reported that Wilkin-
son’s catalyst7n and Tp*Rh(PPh3)2 (I, Figure 1)8 are excellent
catalysts for alkyne hydrothiolation using alkyl thiols to generate
the E-linear and branched alkyl vinyl sulfides, respectively. In
the latter case, the formation of the branched isomer is a
significant departure from the regioselectivity obtained with
other group 9 metal complexes using aryl thiols.7 Given the
apparent generality of the process, we sought to study the
hydrothiolation reaction in greater detail.
We have recently reported a detailed analysis of the ligand
requirements of the pyrazolylborate ligand, along with solution
and solid phase structures of the resulting rhodium complexes.9
Both 3,5-dimethyl pyrazolylborate (Tp*) and 3-phenyl-5-methyl
pyrazolylborate (TpPh,Me) were found to be superior to other
ligands studied. Given the inherent difficulties associated with
the synthesis and purification of the TpPh,Me ligand and resulting
rhodium complex, we elected to use Tp*Rh(PPh3)2 for further
study. We report herein the results of a systematic exploration
of the scope and limitations of hydrothiolation using this catalyst.
Results and Discussion
Our first objective was to evaluate the range of terminal
alkynes that could act as suitable substrates in hydrothiolation.
(4) (a) Paris, J. M.; Barriere, J. C.; Smith, C.; Bost, P. E. In Recent Progress
in the Chemical Synthesis of Antibiotics; Lucas, G., Ohno, M., Eds.; Springer-
Verlag: Berlin, 1990; pp 183-248. (b) Di Giambattista, M.; Chinali, G.; Cocito,
C. J. Antimicrob. Chemother. 1989, 24, 485–488. (c) Cocito, C. Microbiol. ReV.
1979, 43, 145–169.
(5) Radical reactions: (a) Oswald, A. A.; Griesbaum, K.; Hudson, B. E.;
Bregman, J. M. J. Am. Chem. Soc. 1964, 86, 2877–2884. (b) Griesbaum, K.
Angew. Chem., Int. Ed. 1970, 9, 270. (c) Patai, S., Ed.; In The Chemistry of the
Thiol Group; John Wiley & Sons, Ltd.: London, 1974, 2. (d) Ichinose, Y.;
Wakamatsu, K.; Nozaki, K.; Birbaum, J. L.; Oshima, K.; Utimoto, K. Chem.
Lett. 1987, 1647–1650. (e) Capella, L.; Montevecchi, P. C.; Navacchia, M. L. J.
Org. Chem. 1996, 61, 6783–6789.
(6) Nucleophilic reactions: (a) Truce, W. E.; Simms, J. A. J. Am. Chem.
Soc. 1956, 78, 2756–2759. (b) Carson, J. F.; Boggs, L. E. J. Org. Chem. 1966,
31, 2862–2864. (c) Truce, W.; Tichenor, G. J. W. J. Organomet. Chem. 1972,
37, 2391–2396. (d) Katritzky, A. R.; Ramer, W. H.; Ossana, A. J. Org. Chem.
1985, 50, 847–852. (e) Kondoh, A.; Takami, K.; Yorimitsu, H.; Oshima, K. J.
Org. Chem. 2005, 70, 6468–6473.
a Reaction conditions: 10 mmol alkyne, 11 mmol thiol, 4 mL of 1:1
DCE:PhCH3, and 0.3 mmol (3 mol %) catalyst, at room temperature for
2 h, unless otherwise noted. b Isolated yields. c Reference 7. d An
additional ∼5-10% of an unidentified byproduct was observed.
e Reaction time 24 h. Yield after 2 h is 10%.
(7) Metal-catalyzed reactions: using Mo: (a) McDonald, J. W.; Corbin, J. L.;
Newton, W. E. Inorg. Chem. 1976, 15, 2056–2061using Pd: (b) Ba¨ckvall, J. E.;
Ericsson, A. J. Org. Chem. 1994, 59, 5850–5851. (c) Gabriele, B.; Salerno, G.;
Fazio, A. Org. Lett. 2000, 2, 351–353. (d) Ananikov, V. P.; Orlov, N. V.;
Beletskaya, I. P.; Khrustalev, V. N.; Antipin, M. Y.; Timofeeva, T. V. J. Am.
Chem. Soc. 2007, 129, 7252–7253. (e) Kondoh, A.; Yorimitsu, H.; Oshima, K.
Org. Lett. 2007, 9, 1383–1385using Pd, Rh, Ni, and Pt: (f) Kuniyasu, H.; Ogawa,
A.; Sato, K. I.; Ryu, I.; Kambe, N.; Sonoda, N. J. Am. Chem. Soc. 1992, 114,
5902–5903. (g) Ogawa, A.; Ikeda, T.; Kimura, K.; Hirao, T. J. Am. Chem. Soc.
1999, 121, 5108–5114using Rh and Ir: (h) Burling, S.; Field, L. D.; Messerle,
B. A.; Vuong, K. Q.; Turner, P. J. Chem. Soc., Dalton Trans. 2003, 4181–
4191using Ni: (i) Ananikov, V. P.; Malyshev, D. A.; Beletskaya, I. P.;
Aleksandrov, G. G.; Eremenko, I. L. AdV. Synth. Catal. 2005, 347, 1993–2001.
(j) Ananikov, V. P.; Zalesskiy, S. S.; Orlov, N. V.; Beletskaya, I. P. Russ. Chem.
Bull., Int. Ed. 2006, 55, 2109–2113using Ni and Pd: (k) Malyshev, D. A.; Scott,
N. M.; Marion, N.; Stevens, E. D.; Ananikov, V. P.; Beletskaya, I. P.; Nolan,
S. P. Organometallics 2006, 25, 4462–4470. (l) Ananikov, V. P.; Orlov, N. V.;
Beletskaya, I. P. Organometallics 2006, 25, 1970–1977using Rh: (m) Misumi,
Y.; Seino, H.; Yasushi, M. J. Organomet. Chem. 2006, 691, 3157–3164. (n)
Shoai, S.; Bichler, P.; Kang, B.; Buckley, H.; Love, J. A. Organometallics 2007,
26, 5602–5611. (o) Silva, M.; Lara, R.; Marczewski, J.; Jacob, R.; Lenardao,
E.; Perin, G. Tetrahedron Lett. 2008, 49, 1927–1930.
Benzylthiol, which had been previously shown to react rapidly
and regioselectively with six different alkynes,8 was selected
for initial study. In a typical experiment, PhCH3 (2 mL), DCE
(2 mL) and Tp*Rh(PPh3)2 (280 mg, 0.30 mmol, 3 mol %) were
combined in a 20 mL vial equipped with a magnetic stir bar
and a screw cap. Benzylthiol (1.3 mL, 11 mmol, 1.1 equiv
relative to alkyne) and alkyne (10 mmol, 2.5 M) were then added
and the solution was stirred at room temperature for 2 h. The
choice of a 2 h time limit allowed for the direct comparison of
alkyne reactivity.
The effect of electronics on reactivity and selectivity was
revealed by examining para-substituted phenylacetylenes (Table
1, entries 1-6). All reactions proceeded with high regioselec-
tivity to provide the corresponding branched alkyl vinyl sulfides,
indicating that substitution had little impact on regioselectivity.
In marked contrast, both reaction efficiency and yield were
(8) Cao, C.; Fraser, L. R.; Love, J. A. J. Am. Chem. Soc. 2005, 127, 17614–
17615.
(9) Fraser, L. R.; Bird, J.; Wu, Q.; Cao, C.; Patrick, B. O.; Love, J. A.
Organometallics 2007, 26, 5778–5781.
J. Org. Chem. Vol. 74, No. 1, 2009 183

Yang et al.
TABLE 2. Scope of Hydrothiolation of Aliphatic Alkynes with
Benzylthiol Catalyzed by I
FIGURE 2. ORTEP diagram of complex II. Thermal ellipsoids are
drawn at the 50% probability level. Hydrogen atoms, except for the
B-H hydrogen and the phenyl groups of PPh3, are excluded for clarity.
Selected bond lengths (Å), angles (deg) and crystallographic data are
given in Supporting Information.
profoundly influenced by electronic modifications. Hydrothi-
olation of both electron-rich (entries 1-3) and unsubstituted
(entry 4) phenylacetylenes proceeded in excellent yields,
whereas electron-deficient alkynes (entry 5 and 6) provided
inferior yields.
a Reaction conditions: 10 mmol alkyne, 11 mmol thiol, 4 mL of 1:1
DCE:PhCH3, and 0.3 mmol (3 mol %) catalyst, rt. b Isolated yields.
c Reference 7.
Having established that para-substitution plays a crucial role
in reactivity but not selectivity, the effect of substitution at both
the meta- and ortho- positions was next addressed. As antici-
pated, only the branched isomer was observed in each reaction
(entries 7-9). The incorporation of a methoxy group in the
meta-position was well-tolerated (entry 7), whereas the use of
2-methoxyphenylacetylene provided a mere 55% yield after 24 h
(entry 8). The lower yield in the latter case could be a
consequence of greater steric hindrance at the ortho position.
Alternatively, coordination of the methoxy oxygen to rhodium
could impede catalysis. To differentiate between these scenarios,
ortho-methylphenylacetylene was examined, as the methyl
substituent has a greater steric demand than methoxy, but a
substantially lower propensity for coordination to rhodium. The
methyl-substituted alkyne (entry 9) reacted with benzylthiol with
considerably higher efficiency and in higher yield than did ortho-
methoxyphenylacetylene (entry 8). As such, we concluded that
oxygen coordination was responsible for both the lower yield
and turnover rate with ortho-methoxyphenylacetylene.
Consistent with this analysis, 2-pyridylacetylene was unre-
active in hydrothiolation (entry 10). Further insight was obtained
from the stoichiometric reaction of Tp*Rh(PPh3)2 (93 mg, 0.1
mmol) and 2-pyridylacetylene (0.1 mL, 1.0 mmol) in d8-toluene
crystals suitable for X-ray-analysis. The ORTEP diagram, shown
in Figure 2, indicates that the alkyne underwent activation of
the alkynyl C-H bond to generate a rhodium hydrido acetylide
(II). We10 and others11 have found this process to be quite facile
for a number of alkynes in the presence of Tp*Rh(PPh3)2. With
respect to the hydrothiolation reaction, we hypothesize that
coordination of pyridine precludes the reaction of thiol, thereby
presenting an opportunity for the rhodium species to activate
the alkynyl C-H bond. Further evidence for this suggestion
was obtained by evaluating the effect of 2-pyridylacetylene as
a catalyst poison. Addition of 1 equiv of 2-pyridylacetylene to
a typical reaction of benzylthiol and phenylacetylene precluded
catalysis. This result suggests that the reaction of 2-pyridy-
lacetylene with Tp*Rh(PPh3)2 is more rapid than hydrothiolation
and that the C-H activation is irreversible. In comparison, C-H
activation of the alkynyl C-H bond of o-methoxyphenylacety-
lene is considerably slower than with 2-pyridylacetylene. Thus,
we conclude that the methoxy group slows productive hydrothi-
olation but does not completely shut down catalysis. A possible
explanation for the lower yield with o-methyoxyphenylacetylene
as compared with the para-isomer is that the catalyst is slowly
depleted from the reaction by C-H activation.
1
(1 mL). The reaction was monitored by both H and 31P NMR
spectroscopy. Within 30 min, the PPh3 resonance of
Tp*Rh(PPh3)2 (δ 42.92, d, J ) 175.6 Hz) disappeared and a
new doublet emerged (δ 45.90, JRh-P ) 124.7 Hz). The 1H NMR
spectrum indicated the appearance of a rhodium hydride species
(δ -14.68, JRh-H ) 20.5 Hz, JP-H ) 17.6 Hz). This phenomenon
was also observed in the attempted catalytic reaction. Transfer
of the d8-toluene solution to a 5 mL vial, followed by layering
with 2 mL hexanes, provided, after 2 days at room temperature,
Given the importance of electronic and steric effects in the
reactivity of substituted arylacetylenes, we were eager to
evaluate the reactivity of nonaromatic alkynes (Table 2). In
general, aliphatic alkynes required longer reaction times to reach
completion than aryl alkynes. Importantly, a variety of poten-
tially reactive functional groups were well-tolerated in this
reaction, including nitriles, halogens, ethers, esters and silanes.
184 J. Org. Chem. Vol. 74, No. 1, 2009

Synthesis of 1,1-Disubstituted Alkyl Vinyl Sulfides
TABLE 3. Scope of Hydrothiolation of Phenylacetylene with
Different Thiols Catalyzed by I
Good-to-excellent yields of product were obtained for all alkynes
studied, with the exception of phenyl propargyl ether (entry 5).
The lower yield in this case may result from slower turnover
due to coordination of the ether moiety to rhodium.
We had previously disclosed that vinyl sulfides containing
propargylic protons are prone to isomerization to the corre-
sponding internal vinyl sulfide. For example, benzyl(1-ben-
zylvinyl)sulfane (10a), the product of entry 1, was found to
isomerize to the internal alkyl vinyl sulfides upon standing in a
chloroform solution overnight (eq 2), presumably due to trace
amounts of HCl.8 This isomerization is suppressed by avoiding
chloroform as a solvent for either chromatography or NMR
spectroscopic studies (eq 3). Purification of chloroform prior
to use also precludes isomerization.
The product indicated in entry 6 and its oxidized derivatives
are potential Diels-Alder substrates. Although rhodium catalysts
have been reported to promote the [4 + 2] cycloaddition of
dienes,12 the cycloaddition of the product of 1-ethynylcyclo-
hexene with either remaining alkyne or vinyl sulfide product
was not observed under the reaction conditions. The effect of
sterically bulky groups on hydrothiolation efficiency was also
investigated (entries 7 and 8). Both tert-butylacetylene and
trimethylsilylacetylene reacted efficiently, although high regi-
oselectivity was achieved only in the former case. Nevertheless,
the vinyl silane products (entry 8) can potentially be further
functionalized in Hiyama13 cross-coupling or deprotected to
yield the monosubstituted vinyl sulfide. Of additional interest,
the regioselectivity of the reaction reverses when electronically
activated alkynes, such as ethyl propiolate, are used (entry 9).
In this case, a 2:1 ratio of E- and Z-linear isomers was formed.14
Having established that a broad range of terminal alkynes
could undergo efficient hydrothiolation with high regioselec-
tivity, we were poised to investigate the scope of thiols that
could participate in the reaction (Table 3). Both sterically
undemanding (entries 1 and 2) and bulky thiols (entry 3) provide
the corresponding branched vinyl sulfide in good yields.
Consistent with our findings regarding alkynyl substituents, a
variety of functional groups are tolerated in the reaction,
a Reaction conditions: 10 mmol alkyne, 11 mmol thiol, 4 mL of 1:1
DCE:PhCH3, and 0.3 mmol (3 mol %) catalyst, at rt for 2 h, unless
otherwise noted. b Isolated yields. c Reference 7. d Reference 2f.
e Reaction time: 24 h.
including heteroaromatic groups, ethers, esters and unprotected
amines (entries 4-7, respectively). In contrast, the use of a thiol
bearing either a carboxylic acid moiety (entry 8) or an allyl
group (entry 9) was not tolerated. In the latter case, the olefin
must play some role in suppressing catalysis, as n-propylthiol
reacts uneventfully (entry 2). Had the allyl-substituted thiol
successfully reacted, the product could be susceptible to a
number of possible subsequent transformations, including thio-
Cope15 and Mislow-Evans16 rearrangements (upon oxidation to
the sulfoxide). As such, we sought an explanation for the lack
of reactivity of allyl mercaptan under these reaction conditions.
To gain further insight into this issue, we conducted the
following stoichiometric reaction. Tp*Rh(PPh3)2 (93 mg, 0.1
mmol) was dissolved in d8-toluene (1 mL). The resulting
solution was added by pipet to an NMR tube, and allyl
mercaptan (0.08 mL, 1.0 mmol) was added by syringe. The
reaction was monitored by both 1H and 31P NMR spectroscopy.
Within 30 min, the PPh3 resonance of Tp*Rh(PPh3)2 (δ 42.92,
d, J ) 175.6 Hz) disappeared and a new singlet emerged at δ
-4.56, indicating complete dissociation of PPh3. The thiol
methylene signal changed from doublet of doublets (δ 3.16, J
) 7.0 Hz, J ) 7.0 Hz) to a doublet (δ 2.78, J ) 6.9 Hz) with
concomitant loss of the thiol S-H signal. No rhodium hydride
species were observed in the 1H NMR spectrum. Although we
were unable to isolate this new species, the data are consistent
(10) Cao, C.; Wang, T.; Patrick, B. O.; Love, J. A. Organometallics 2006,
25, 1321–1324.
(11) (a) Keim, W. J. Organomet. Chem. 1968, 14, 179–184. (b) Barcelo,
F. L.; Besteiro, J. C.; Lahuerta, P.; Foces-Foces, C.; Cano, F. H.; Martinez-
Ripoll, M. J. Organomet. Chem. 1984, 270, 343–351. (c) Knobler, C. B.; King,
R. E., III.; Hawthorne, M. F. Acta Crystallogr., Sect. C 1986, C42, 159–161.
(d) Barcelo, F.; Lahuerta, P.; Ubeda, M. A.; Foces-Foces, C.; Cano, F. H.;
Mart´ınez-Ripoll, M. J. Organomet. Chem. 1986, 301, 375–384. (e) Barcelo, F.;
Lahuerta, P.; Ubeda, M. A.; Cantarero, A.; Sanz, F. J. Organomet. Chem. 1986,
309, 199–208. (f) Bianchini, C.; Masi, D.; Meli, A.; Peruzzini, M.; Zanobini, F.
J. Am. Chem. Soc. 1988, 110, 6411–6423. (g) Lahuerta, P.; Latorre, J.; Mart´ınez-
Manez, R.; Garcia- Granda, S.; Gomez-Beltran, F. Inorg. Chim. Acta 1990, 168,
149–152. (h) Lahuerta, P.; Latorre, J.; Mart´ınez-Manez, R.; Paya, J.; Tiripicchio,
A.; Tiripicchio Camellini, M. Inorg. Chim. Acta 1993, 209, 177–186. (i) Bennett,
M. A.; Bhargava, S. K.; Ke, M.; Willis, A. C. J. Chem. Soc., Dalton Trans.
2000, 3537–3545.
(15) Yoshinao, T.; Toshiro, H.; Zenichi, Y. J. Am. Chem. Soc. 1980, 102,
2392–2398.
(16) (a) Deborah, K. J. H.; William, L. J. J. Am. Chem. Soc. 1995, 117,
9077–9078. (b) Bickart, P.; Carson, F. W.; Jacobus, J.; Miller, E. G.; Mislow,
K. J. Am. Chem. Soc. 1968, 90, 4869–4876. (c) Evans, D. A.; Andrew, G. C.;
Simis, C. L. J. Am. Chem. Soc. 1971, 93, 4956–4957.
(12) Chumachenko, N.; Sampson, P.; Hunter, A. D.; Zeller, M. Org. Lett.
2005, 7, 3203–3206.
(13) Hatanaka, Y.; Hiyama, T. J. Org. Chem. 1988, 53, 918–920.
(14) No reaction occurs in the absence of catalyst. The use of DBU generates
a 1:2 ratio of E- and Z-linear isomers after 2 h at rt.
J. Org. Chem. Vol. 74, No. 1, 2009 185

Yang et al.
TABLE 4. Scope of Hydrothiolation of Different Alkynes with
n-Propanethiol Catalyzed by I
with the formation of a rhodium dithiolate that is inactive in
hydrothiolation. Such a species has been identified by Mizobe
and co-workers in related hydrothiolation studies.17 Consistent
with this analysis, a small amount of diallyldisulfide was formed,
as evidenced by comparison of the 1H NMR spectrum with an
authentic sample. Our hypothesis is that the presence of the
olefin of allyl mercaptan, in comparison to n-propanethiol, which
undergoes productive hydrothiolation, provides additional stabil-
ity to the resulting rhodium species, precluding catalysis.
Alternatively, the olefin may result in the rhodium complex
following an entirely different pathway than other thiols. We
are currently investigating the detailed reaction mechanism to
provide additional information about this surprising result.
We have also found that addition of 1 equiv of allyl mercaptan
to a typical reaction of benzylthiol, phenylacetylene and
Tp*Rh(PPh3)2 completely shuts down catalysis. This result
indicates that the reaction of allyl mercaptan with Tp*Rh(PPh3)2
is more rapid than hydrothiolation and is also irreversible. This
is consistent with poisoning of the catalyst by allyl mercaptan.
We therefore considered the possibility that the carboxylic acid
(entry 8) could also be poisoning the catalyst. However, addition
of 1 equiv of acetic acid to a typical reaction of benzylthiol,
phenylacetylene and Tp*Rh(PPh3)2 had no effect on catalysis;
it is worth noting that we have previously found that neither
organic nor mineral acids catalyze hydrothiolation.8 Thus, our
hypothesis is that the lack of reactivity of is due to coordination
of the carboxylic acid.
a Reaction conditions: 10 mmol alkyne, 11 mmol thiol, 4 mL of 1:1
DCE:PhCH3, and 0.3 mmol (3 mol %) catalyst, rt. b Reference 2f.
c Isolated yields.
The catalytic hydrothiolation of n-propanethiol and various
alkynes was also investigated.2f Consistent with expectation,
all reactions proceeded with high selectivity. Likewise, the
reaction of para-substituted phenylacetylenes followed the same
trends observed for benzyl thiol, with electron-rich alkynes
reacting rapidly and electron-deficient alkynes proceeding more
slowly and in lower yields (Table 4, entries 1-4). Both aliphatic
alkynes examined reacted in high isolated yields and with high
selectivity (entries 5-7). The resulting n-propyl vinyl sulfides
have proven to be suitable substrates for Kumada-type cross-
coupling to generate 1,1-disubstituted olefins.2f,18
equiv of 4-ethynylanisole in the presence of 3 mol % of
Tp*Rh(PPh3)2 to generate the desired product in 80% isolated
yield after 24 h at rt (eq 4). No evidence for formation of the
monofunctionalized vinyl sulfide was detected.
We next explored the catalytic hydrothiolation of internal
alkynes. Unlike terminal alkynes, which react rapidly within
2 h at rt, hydrothiolation of internal alkynes typically requires
elevated temperatures and/or extended reaction times (Table 5).
For example, cyclopentylthiol reacted with diphenylacetylene
to provide the corresponding vinyl sulfide as a single isomer in
94% yield (entry 1). In contrast, the reaction of benzylthiol only
produced trace amounts of the expected product (entry 2). When
3-hexyne was used as the alkyne, an additional complication
arose. The desired vinyl sulfide was obtained in only 32% yield
(entry 3); hexaethylbenzene, was formed by cyclotrimerization
in 20% yield.19 Elevated temperatures did not facilitate the
reactions shown in either entries 2 or 3. The reaction of an
unsymmetrical internal alkyne proceeded with modest regiose-
lectivity in favor of the less-hindered isomer (entry 4).
In conclusion, Tp*Rh(PPh3)2 successfully catalyzes the hy-
drothiolation a wide variety of thiols and alkynes, including both
terminal and internal alkynes. In general, the reactions proceed
in good to excellent yields, and the branched isomer is
predominates in most cases. A broad range of functional groups
are tolerated, including halides, amines, nitriles, amines, ethers,
esters and silanes. Strongly coordinating groups, such as
pyridine, hinder catalysis. Our current efforts are focused on
delineating the reaction mechanism, exploring the use of this
methodology in the synthesis of bioactive molecules and
generating catalysts capable to promoting hydrothiolation of
recalcitrant substrates.
Our final goal was to demonstrate the viability of a bis-thiol
to undergo hydrothiolation. 1,6-Hexanedithiol reacted with 2.2
Experimental Section
(17) Misumi, Y.; Seino, H.; Mizobe, Y. J. Organomet. Chem. 2006, 691,
3157–3164.
(18) (a) Wenkert, E.; Fernandes, J. B.; Michelotti, E. L.; Swindell, C. S.
Synthesis 1981, 701–703. (b) Wenkert, E.; Shepard, M. E.; Mcphail, A. T.
J. Chem. Soc. Chem. Commun. 1986, 13, 1390–1391. (c) Okamura, H.; Miura,
M.; Takei, H. Tetrahedron Lett. 1979, 1, 43–46.
Materials and Methods. Hexanes (boiling range 68.3-69.6 °C),
CH2Cl2, benzene, DCE (1,2-dichloroethane), Et2O, THF and PhCH3
were dried by passage through solvent purification columns.20
(19) (a) Amer, I.; Bernstein, T.; Eisen, M.; Blum, J.; Vollhardt, K. P. C. J.
Mol. Catal. 1990, 60, 313–321.
(20) (b) Agenet, N.; Gandon, V.; Vollhardt, K. P. C.; Malacria, M.; Aubert,
C. J. Am. Chem. Soc. 2007, 129, 8860–8871.
186 J. Org. Chem. Vol. 74, No. 1, 2009

Synthesis of 1,1-Disubstituted Alkyl Vinyl Sulfides
TABLE 5. Scope of Hydrothiolation of Internal Alkynes Catalyzed by I
a Reaction conditions: 10 mmol alkyne, 11 mmol thiol, 4 mL of 1:1 DCE:PhCH3, and 0.3 mmol (3 mol %) catalyst. b Isolated yields. c Reference 7.
d
Yield based on H NMR analysis. e Note that 33b is identical to 10a′′ (eq 3).
1
CDCl3 was distilled from P2O5 and was degassed prior to use. C6D6
was purified by vacuum transfer from Na/benzophenone. All organic
reagents were obtained from commercial sources and used as
received. Wilkinson Catalyst was purchased from Strem Chemicals
and was used without further purification. Tp*Rh(PPh3)2 (I)21 was
prepared as previously reported.9
300 MHz): δ 7.56-7.53 (m, 2H), 7.39-7.33 (m, 4H), 6.29-6.27
(m, 1H), 6.10 - 6.09 (m, 1H), 5.49 (s, 1H), 5.31 (s, 1H), 3.88 (s,
2H). 13C{1H} NMR (CDCl3, 75 MHz): δ 150.8, 144.4, 142.2, 139.2,
128.6, 128.5, 127.5, 113.5, 110.6, 107.8, 31.1. HRMS (EI) m/z calcd
for C13H12SO: 216.0609; found: 216.0606. Anal. calcd for
C13H12SO: C, 72.19; H, 5.59; found: C, 72.45; H, 5.60.
General Experimental Procedure for Hydrothiolation.
Tp*Rh(PPh3)2 (280 mg, 0.30 mmol, 3 mol %), PhCH3 (2 mL), DCE
(2 mL) were combined in the glovebox in a 20 mL vial equipped
with a magnetic stir bar and a screw cap. Thiol (11 mmol) and
alkyne (10 mmol) were added sequentially. The vial was removed
from the glovebox. The vial was then wrapped in aluminum foil
and the solution was stirred at room temperature and monitored by
TLC. After the reaction was completed, the resulting mixture was
filtered through silica gel, washed by hexanes, concentrated under
vacuum. Flash chromatography (SiO2, hexanes or a mixture of
hexanes: EtOAc as eluent) provided the product. Note: The reactions
proceed very slowly in the absence of the catalyst, indicating that
background reactions are minimal. The addition of a non-nucleo-
philic base (2,2-lutidine) does not impede or improve the reaction.8
Analytical data for 2a, 4a, 13a, 15a, 16a, 19a, 20a, 31a, and 33a,b
were previously reported.8 Representative examples of data for new
compounds are given below.
Synthesis of Complex II. In glovebox, a solution of Tp*Rh(PPh3)2
(93 mg, 0.1 mmol) in toluene (1 mL) were combined in the
glovebox in a 5 mL vial equipped with a screw cap and a magnetic
stir bar. 2-pyridylacetylene (0.1 mL, 1.0 mmol) was added by
syringe to the solution. The mixture was stirred for 2 h at room
temperature, followed by layering with 2 mL hexanes. After 2 days,
brown crystals formed. The solution was decanted, and the crystals
were washed with 2 × 1 mL of hexanes. The product was dried
under reduced pressure to give 50 mg (65%) of an brown crystalline
1
solid. H NMR (CD2Cl2, 400 MHz) at 25 °C: δ 8.19 (d, 1H, J )
3.9 Hz) 7.60 (m, 6H),7.42-7.33 (m, 4H), 7.24-7.20 (m, 6H),
7.70-6.90 (m, 2H), 5.71 (d, 2H, J ) 8.8 Hz), 5.17 (s, 1H), 2.72
(s, 3H), 2.50 (s, 3H), 2.30 (s, 3H), 2.25 (s, 3H), 1.44 (s, 3H), 1.37
(s, 3H), δ -14.68 (q, 1H, JRh-H ) 20.5 Hz, JP-H ) 17.6 Hz), B-H
not observed. 13C{1H} NMR (CD2Cl2, 100 MHz): δ 154.5, 150.8,
149.8, 147.8, 145.5, 144.5, 135.9, 135.8, 135.6, 133.8, 133.4, 130.5,
128.2, 128.1, 126.1, 119.7, 107.5, 106.3, 106.1, 16.5, 13.2, 12.9,
12.1. 31P{1H} NMR (CD2Cl2, 121 MHz): δ 37.69 (JRh-P ) 130.8
Hz). HRMS (EI) m/z calcd for C40H42BN7PRh: 765.2387; found:
765.2389.
Benzyl(1-(4-N,N-dimethyphenylvinyl)sulfane (1a). Yellow oil.
Column chromatography conditions: 20:1 hexanes:EtOAc and 3%
1
Et3N. H NMR (CDCl3, 300 MHz): δ 7.47 (d, 2H, J ) 8.7 Hz),
7.31-7.23 (m, 5H), 6.71 (d, 2H, J ) 9.1 Hz), 5.36 (s, 1H), 5.08
(s, 1H), 3.90 (s, 2H), 2.99 (s, 6H). 13C{1H} NMR (CDCl3, 100
MHz): δ 149.3, 145.7, 138.5, 129.9, 129.4, 129.1, 128.2, 128.0,
113.0, 110.1, 41.5, 38.2. HRMS (EI) m/z calcd for C17H19SN:
269.1238; found: 269.1236. Anal. calcd for C17H19SN: C, 75.79;
H, 7.11; N, 5.20; found: C, 75.72; H, 7.16; N, 5.53.
Acknowledgment. We thank the following for support of
this research: University of British Columbia, NSERC (Dis-
covery Grant, Research Tools and Instrumentation Grants),
Merck Frosst, the Canada Foundation for Innovation and the
British Columbia Knowledge Development Fund.
2-((1-Phenylvinylthio)methyl)furan (21a). Yellow oil. Column
chromatography conditions: 20:1 hexanes:EtOAc. 1H NMR (CDCl3,
Supporting Information Available: Analytical data, NMR
spectra for all new compounds, and X-ray report for complex
II. This material is available free of charge via the Internet at
http://pubs.acs.org.
(21) Pangborn, A. B.; Giardello, M. A.; Grubbs, R. H.; Rosen, R. K.;
Timmers, F. J. Organometallics 1996, 15, 1518–1520.
(22) (a) Connelly, N. G.; Emslie, D. J. H.; Geiger, W. E.; Hayward, O. D.;
Linehan, E. B.; Orpen, A. G.; Quayle, M. J.; Rieger, P. H. J. Chem. Soc., Dalton
Trans. 2001, 670–683. (b) Cˆırcu, V.; Fernandes, M. A.; Carlton, L. Inorg. Chem.
2002, 41, 3859–3865.
JO801644S
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